title: Interleukin-7 mediates selective expansion of tumor-redirected cytotoxic T lymphocytes (CTLs) without enhancement of regulatory T-cell inhibition.
abstract: OBJECTIVE
  The antitumor activity of chimeric antigen receptor (CAR)-redirected CTLs should be enhanced if it were possible to increase their proliferation and function after adoptive transfer without concomitantly increasing the proliferation and function of regulatory T cells (Treg). Here, we explored whether the lack of IL-7Rα in Treg can be exploited by the targeted manipulation of the interleukin-7 (IL-7) cytokine-cytokine receptor axis in CAR-engrafted Epstein-Barr Virus-specific CTLs (EBV-CTLs) to selectively augment their growth and antitumor activity even in the presence of Treg.
  
  
  METHODS
  We generated a bicistronic retroviral vector encoding a GD2-specific CAR and the IL-7Rα subunit, expressed the genes in EBV-CTLs, and assessed their capacity to control tumor growth in the presence of Treg in vitro and in vivo when exposed to either interleukin-2 (IL-2) or IL-7 in a neuroblastoma xenograft.
  
  
  RESULTS
  We found that IL-7, in sharp contrast with IL-2, supports the proliferation and antitumor activity of IL-7Rα.CAR-GD2(+) EBV-CTLs both in vitro and in vivo even in the presence of fully functional Treg.
  
  
  CONCLUSIONS
  IL-7 selectively favors the survival, proliferation, and effector function of IL-7Rα-transgenic/CAR-redirected EBV-CTLs in the presence of Treg both in vitro and in vivo. Thus, IL-7 can have a significant impact in sustaining expansion and persistence of adoptively CAR-redirected CTLs.
authors.affiliation: Authors' Affiliations: Center for Cell and Gene Therapy, and Departments of Pediatrics, Immunology, and Medicine, Baylor College of Medicine, Methodist Hospital and Texas Children's Hospital, Houston, Texas; Dipartimento di Ematologia ed Oncologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy.
authors.forename: Serena K
authors.initials: SK
authors.lastname: Perna
authors.forename: Daria
authors.initials: D
authors.lastname: Pagliara
authors.forename: Aruna
authors.initials: A
authors.lastname: Mahendravada
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.forename: Barbara
authors.initials: B
authors.lastname: Savoldo
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017252:CD3 Complex / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D015851:Interleukin-7 / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000235:genetics; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D047368:Tumor Burden / Q000276:immunology
chemical_list: D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; C508605:IL7 protein, human; D015851:Interleukin-7; D011948:Receptors, Antigen, T-Cell; D020395:Receptors, Interleukin-7; D011993:Recombinant Fusion Proteins; C415350:interleukin-7 receptor, alpha chain